Peripheral neuropathy is the most common neurological complication of HIV infection with the prevalence of neuropathy as high as 69.4% in HIV-infected patients. Increasing reports from humans highlight the contribution of macrophage activation and dorsal root ganglia (DRG) inflammation to the persistence of pathological pain in peripheral neuropathy, but the demonstration of macrophage traffic and DRG macrophages as a viral reservoir is not known. The pathogenesis of peripheral neuropathy is incompletely understood, but it is likely macrophage-mediated. In this application, we will use a SIV rhesus macaque model of AIDS to determine if: 1) continual monocyte traffic to DRGs drives peripheral neuropathy pathogenesis and effective anti-retroviral therapy (ART) will minimize this effect, 2) the ratio of M1/M2 regulatory predicts early versus chronic peripheral nerve lesions and effective ART will alter this ratio, 3) clinically relevant biomarkers (sCD163, BrdU, IENF) are linked to DRG pathology, and 4) DRG macrophages are viral reservoirs with and without ART. Successful completion of studies in this application will allow us to define: 1) monocyte/ macrophage mechanisms of DRG pathology, 2) monocyte/macrophage immune regulation during PNS disease, 3) clinical markers of peripheral nerve disease and 4) DRG macrophages as active sites of viral replication and as viral reservoirs. The overall hypothesis of the application is continual monocyte/macrophage traffic drives DRG pathogenesis and clinically relevant biomarkers and IENF effectively predict peripheral nerve pathology with and without ART. Studies in aim 1 will define the role of monocyte traffic and macrophage turnover driving PNS pathogenesis and establish a correlation between DRG damage and IENF loss with the hypothesis that monocyte traffic to DRGs mediates damage and correlates to PNS pathology. A subaim will address the hypothesis that the ratio of M1/M2 macrophages predicts early versus chronic PNS lesions. Additionally, DRG macrophages as active sites of viral replication and/or as latent viral reservoirs will be defined in this aim. Studies in aim 2 will define the role of systemic viral suppression to: 1) stop or slow PNS disease; 2) stop or slow macrophage recruitment to DRGs and 3) to clear DRG viral reservoirs. The hypothesis driving aim 2 is that systemic viral suppression by ART will slow PNS disease progression by inhibiting monocyte traffic to the DRGs and potentially clear DRG viral reservoirs. The studies described in this application provide an exciting opportunity to define the role of monocyte/macrophage traffic and macrophage activation in PNS disease and neuronal injury and the role of systemic viral immune suppression. The studies proposed here will provide new avenues of investigation into the development of therapies targeting the monocyte/macrophage in HIV peripheral neuropathy. PUBLIC HEALTH RELEVANCE: HIV-associated peripheral neuropathy is the most common neurological complication of HIV infection with prevalence as high as 69.4% in HIV-infected patients. In this application, we will use a SIV rhesus macaque model of AIDS to define the role of monocyte traffic driving peripheral nerve pathogenesis, to predict the formation of early versus chronic peripheral nerve lesions using the ratio of M1/M2 regulatory macrophages and to examine clinical biomarkers (sCD163, BrdU, IENF) linked to DRG pathology. Studies in this application will allow us to define mechanisms of DRG pathology, monocyte/macrophage immune regulation during peripheral nerve system disease and the ability of effective antiretroviral therapy to stop monocyte traffic and to clear DRG macrophage reservoirs.